Due to the multidisciplinary nature and complexity of selffolding structures, it can be difficult to know where to start when designing for a new application. Decisions about the active and passive materials to be used and the functionality of the design are very interrelated and can create problems if not considered holistically. There is a need to formalize the steps necessary to move from an origami-inspired shape to a full self-folding concept. In this paper, an optimization framework is proposed to help designers create self-folding, origami-inspired structures that can accommodate any type of active material. The optimization framework formalizes the design steps needed to move from a target shape/application to a self-folding design. The method is simulation-based, allowing a self-folding design candidate to be identified quickly prior to costly trial-and-error physical prototyping. A general version of the framework is presented that can accommodate a variety of simulation and optimization methods, after which a specific implementation of the framework utilizing a dynamic model and trade space exploration tools is discussed and then used to design a multi-field self-folding carton. By using the framework, a novel design was identified that both significantly decreased the folding error as well as the amount of active material used when compared to designs that would typically be attempted in a trial-by-error design approach. The demonstrated self-folding design optimization framework has the potential to streamline the design of self-folding structures, resulting in better designs with less time, effort, and cost.